Formation of chiral 4-chromanones using chiral pyrrolidines in the presence of acids

ABSTRACT

The present invention relates to a synthesis of chromanones or chromanes in a stereospecific matter in view of the 2-position in the chromanone or chromane ring. It has been found that this synthesis is particularly possible in the presence of a chiral compound of a specific type and of at least one Bransted acid or in the presence a specific chiral compound having a Bransted acid functional group in the molecule.

TECHNICAL FIELD

The present invention relates to the field of the synthesis oftocopherols and tocotrienols.

BACKGROUND OF THE INVENTION

Chromane compounds represent an important class of chiral naturalproducts and bioactive compounds. An important class of chromanecompounds are vitamin E and its esters. Often vitamin E iscommercialized in the form of its esters because the latter show anenhanced stability.

On the one hand the typical technical synthesis of vitamin E leads tomixtures of isomers. On the other hand higher bioactivity (biopotency)has been shown to occur in general by tocopherols and tocotrienolshaving the R-configuration at the chiral centre situated next to theether atom in the ring of the molecule (indicated by * in the formulasused later on in the present document) (i.e. 2R-configuration), ascompared to the corresponding isomers having S-configuration.Particularly active are the isomers of tocopherols having the naturalconfiguration at all chiral centres, for example (R,R,R)-tocopherols, ashas been disclosed for example by H. Weiser et al. in J. Nutr. 1996, 126(10), 2539-49. This leads to a strong desire for an efficient processfor separating the isomers. Hence, the isomer separation not only ofvitamin E, but also of their esters, particularly their acetates, aswell as of their precursors is of prime interest.

Separation of all the isomers by chromatographic methods is extremelydifficult and costly.

To overcome these inherent problems, it has been tried to offerstereospecific synthesis allowing the preferential formation of thedesired isomers only. However, these methods are very expensive, complexand/or exotic as compared to the traditional industrial synthesisleading to isomer mixtures.

Therefore, there exists a large interest in providing stereospecificsynthesis routes leading to the desired isomer.

Particular difficult is to achieve specifically the desired chirality atthe chiral carbon centre in the 2-position of the chromane ring.

A synthetic pathway for chromanes is via their correspondingchromanones. It is known from Kabbe and Heitzer, Synthesis 1978; (12):888-889 that α-tocopherol can be synthesized via α-tocotrienol from4-oxo-α-tocotrienol which is accessible from2-acetyl-3,5,6-trimethylhydroquinone and farnesyl-acetone in thepresence of pyrrolidine. However, this procedure leads to a racemicmixture in view of the configuration at the 2-position of the chromanerespectively chromanone ring.

SUMMARY OF THE INVENTION

Therefore, the problem to be solved by the present invention is to offera method for the synthesis of chromanones or chromanes, i.e. ofcompounds of formula (I) or (V) in a stereospecific matter in view ofthe 2-position in the chromanone or chromane ring.

Surprisingly, it has been found that a process for the manufacturingaccording to claim 1 is able to solve this problem.

It has been particularly found that the combination of a specific chiralcompound and a specific Brønsted acid or Brønsted acid group leads tothe formation of the desired product and a desired stereoselectiveformation. Particularly, the desired isomer is formed in preference overthe non-desired isomer yielding to an enantiomeric ratio being largerthan zero or a ratio of [2R]-stereoisomers to [2S]-stereoisomers beinglarger than one.

Further aspects of the invention are subject of further independentclaims. Particularly preferred embodiments are subject of dependentclaims.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the present invention relates to a process for themanufacturing of a compound of formula (I)

comprising the step of reacting a compound of formula (II-A) and acompound of formula (II-B) or a ketal thereof in the presence of anorganic solvent and

either

-   -   of at least one chiral compound of formula (II-C) and of at        least one Brønsted acid having a pK_(a) of between 5 and 10.5,        measured at 25° C. in DMSO;

Or

-   -   of at least one chiral compound of formula (II-C-A) having a        pK_(a) of between 5 and 10.5, measured at 25° C. in DMSO, or an        internal salt thereof

wherein R¹, R³ and R⁴ are independently from each other hydrogen ormethyl groups;

R² and R^(2′) represents hydrogen or a phenol protection group;

R⁵ represents either a linear or branched completely saturatedC₆₋₂₅-alkyl group or a linear or branched C₆₋₂₅-alkyl group comprisingat least one carbon-carbon double bond;

Y¹ represents either CH₂Y² or

-   -   wherein R⁶ represents a linear or branched C₁₋₁₂-alkyl group        which optionally further comprises at least one aromatic group        and/or C═O and/or NH and/or NH₂ group;    -   Y² represents either OH or OR⁷ or NHR⁷ or NHCOOR⁷ or

-   -   wherein R⁷ represents either        -   a linear or branched C₁₋₁₂-alkyl group which optionally            further comprises at least one aromatic group and/or C═O            and/or NH and/or NH₂ group    -   Or        -   an aryl group or a substituted aryl group or a heteroaryl            group or a substituted heteroaryl group

and A represents a substituent carrying a Brønsted acid functional groupand the dotted line(s) represents the bond(s) by which the correspondingsubstituent is bound to the rest of formula (II-C);

and wherein * represents the chiral centre of the chiral isomer offormula (I).

The term “independently from each other” in this document means, in thecontext of substituents, moieties, or groups, that identicallydesignated substituents, moieties, or groups can occur simultaneouslywith a different meaning in the same molecule.

A “C_(x-y)-alkyl”, resp. “C_(x-y)-acyl” group, is an alkyl resp. an acylgroup comprising x to y carbon atoms, i.e. for example an C₁₋₃-alkylgroup, is an alkyl group comprising 1 to 3 carbon atoms. The alkyl resp.the acyl group can be linear or branched. For example —CH(CH₃)—CH₂—CH₃is considered as a C₄-alkyl group.

A “C_(x-y)-alkylene” group is an alkylene group comprising x to y carbonatoms, i.e., for example C₂-C₆ alkylene group is an alkyl groupcomprising 2 to 6 carbon atoms. The alkylene group can be linear orbranched. For example the group —CH(CH₃)—CH₂— is considered as aC₃-alkylene group.

The term “hydrogen” means in the present document H and not H₂.

The sign * in formulae of molecules represents in this document a chiralcentre in said molecule.

In the present document any single dotted line represents the bond bywhich a substituent is bound to the rest of a molecule.

The chirality of an individual chiral carbon centre is indicated by thelabel R or S according to the rules defined by R. S. Cahn, C. K. Ingoldand V. Prelog. This R/S-concept and rules for the determination of theabsolute configuration in stereochemistry is known to the person skilledin the art.

The “pK_(a)” is commonly known as negative decadic logarithm of the aciddissociation constant (pK_(a)=−log₁₀ K_(a)). When the organic acid hasseveral protons the pK_(a) as used in this document relates to thedissociation constant of the first proton (K_(a1)). The pK_(a) ismeasured at 25° C. in DMSO. The method of measuring the pK_(a) at 25° C.in DMSO is described in detail in J. Am. Chem. Soc. 1975, 97, 7006-7014.All values of pK_(a) given in this document are to be determinedaccording to said method.

The residue R⁵ represents either a linear or branched completelysaturated C₆₋₂₅-alkyl group or a linear or branched C₆₋₂₅-alkyl groupcomprising at least one carbon-carbon double bond.

Preferably the group R⁵ is of formula (III).

In formula (III) m and p stand independently from each other for a valueof 0 to 5 provided that the sum of m and p is 1 to 5. Furthermore, thesubstructures in formula (III) represented by S1 and s2 can be in anysequence. The dotted line represents the bond by which the substituentof formula (III) is bound to the rest of the compound of formula (II-B)or formula (I). Furthermore, # represents a chiral centre, obviouslyexcept in case where said centre is linked to two methyl groups.

It is preferred that group R⁵ is of formula (III-x).

As mentioned above the substructures in formula (III) represented by s1and s2 can be in any sequence. It is, therefore, obvious that in casethat the terminal group is having the substructure s2, this terminalsubstructure has no chiral centre.

-   -   In one preferred embodiment m stands for 3 and p for 0.    -   In another preferred embodiment p stands for 3 and m for 0.

Therefore, R⁵ is preferably of formula (III-A), particularly (III-ARR),or (III-B).

Preferred are the following combinations of R¹, R³ and R⁴:

R¹=R³=R⁴=CH₃

or

R¹=R⁴=CH₃, R³=H

Or

R¹=H, R³=R⁴=CH₃

Or

R¹=R³=H, R⁴=CH₃

R² and R^(2′) represents either hydrogen or a phenol protection group.

A phenol protection group is a group which protects the phenolic group(OH in formula (I) or (II-A)) and can be deprotected easily, i.e. bystate-of-the-art methods, to the phenolic group again.

The phenol protection group forms with the rest of the molecule achemical functionality which is particularly selected from the groupconsisting of ester, ether or acetal. The protection group can be easilyremoved by standard methods known to the person skilled in the art.

In case where the phenol protection group forms with the rest of themolecule an ether, the substituent R² or R^(2′) is particularly a linearor branched C₁₋₁₀-alkyl or cycloalkyl or aralkyl group. Preferably thesubstituent R² or R^(2′) is a benzyl group or a substituted benzylgroup, particularly preferred a benzyl group.

In case where the phenol protection group forms with the rest of themolecule an ester, the ester is an ester of an organic or inorganicacid.

If the ester is an ester of an organic acid, the organic acid can be amonocarboxylic acid or a polycarboxylic acid, i.e. an acid having two ormore COOH-groups. Polycarboxylic acids are preferably malonic acid,succinic acid, glutaric acid, adipic acid, maleic acid or fumaric acid.

Preferably the organic acid is a monocarboxylic acid.

Hence, the substituent R² or R^(2′) is preferably an acyl group. Theacyl group is particularly a C₁₋₇-acyl, preferably acetyl,trifluoroacetyl, propionyl or benzoyl group, or a substituted benzoylgroup.

If the ester is an ester of an inorganic acid, the inorganic acid ispreferably nitric acid or a polyprotic acid, i.e. an acid able to donatemore than one proton per acid molecule, particularly selected from thegroup consisting of phosphoric acid, pyrophosphoric acid, phosphorousacid, sulphuric acid and sulphurous acid.

In case where the phenol protection group forms with the rest of themolecule an acetal, the substituent R² or R^(2′) is preferably

with n=0 or 1.

Hence, the acetals formed so are preferably methoxymethyl ether(MOM-ether), β-methoxyethoxymethyl ether (MEM-ether) ortetrahydropyranyl ether (THP-ether). The protection group can easily beremoved by acid.

The protecting group is introduced by reaction of the correspondingmolecule having an R² resp. R^(2′) being H with a protecting agent.

The protecting agents leading to the corresponding phenol protectiongroups are known to the person skilled in the art, as well as thechemical process and conditions for this reaction. If, for example, thephenol protection group forms with the rest of the molecule an ester,the suitable protecting agent is for example an acid, an anhydride or anacyl halide.

In the case that an ester is formed by the above reaction with theprotecting agent, and that said ester is an ester of an organicpolycarboxylic acid or an inorganic polyprotic acid, not necessarily allacid groups are esterified to qualify as protected in the sense of thisdocument. Preferable esters of inorganic polyprotic acids arephosphates.

It is preferred that the protection group R² resp. R^(2′) is a benzoylgroup or a C₁₋₄-acyl group, particularly acetyl or trifluoroacetylgroup. The molecules in which R² resp. R^(2′) represents an acyl group,particularly an acetyl group, can be easily prepared from thecorresponding unprotected molecule by esterification, respectively thephenolic compound can be obtained from the corresponding ester by esterhydrolysis.

It is important to realize that the step of reacting with the protectingagent can occur at different stages of manufacture of compound offormula (I) or of formula (V), the preparation of which is describedlater in this document in more detail, i.e. the reaction can occur forexample at the level of compound of formula (II-A) or before or afterpreparation of compound (I) or compound (V).

It is particularly preferred that R² and R^(2′) is H.

The process of the present invention comprises the steps of reactingcompound of formula (II-A) and compound of formula (II-B) or a ketalthereof.

The corresponding compounds of (II-A) and compound of formula (II-B) ora ketal thereof are easily accessible. For example compounds of (II-A)can be synthesized from the method disclosed in G. Manecke, G. Bourwieg,Chem. Ber. 1962, 95, 1413-1416.

The mentioned reaction between compound of formula (II-A) and compoundof formula (II-B) or a ketal thereof is done in the first embodiment inthe presence of at least one chiral compound of formula (II-C) and of atleast one Brønsted acid having a pK_(a) of between 5 and 10.5, measuredat 25° C. in DMSO.

The group Y¹ represents either CH₂Y² or

R⁶ represents in first instance a linear or branched C₁₋₁₂-alkyl group.Particularly suitable linear or branched C₁₋₁₂-alkyl groups are methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,pentyl, hexyl, heptyl and octyl groups.

R⁶ represents in second instance a linear or branched C₁₋₁₂-alkyl groupwhich comprises further at least one aromatic group and/or C═O and/or NHand/or NH₂ group. Examples of suitable compounds of formula (II-C) forthis embodiment are

y² represents either OH or OR⁷ or NHR⁷ or NHCOOR⁷ or

R⁷ represents in a first instance a linear or branched C₁₋₁₂-alkylgroup. Particularly suitable linear or branched C₁₋₁₂-alkyl groups aremethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,tert-butyl, pentyl, hexyl, heptyl and octyl groups.

R⁷ represents in a second instance a linear or branched C₁₋₁₂-alkylgroup which further comprises at least one aromatic group and/or C═Oand/or NH and/or NH₂ group.

R⁷ represents in a third instance an aryl group or a substituted arylgroup or a heteroaryl group or a substituted heteroaryl group. The arylgroup or a substituted aryl group or a heteroaryl group or a substitutedheteroaryl group is particularly

It is preferred that the compound of formula (II-C) is selected from thegroup consisting of

The compounds of formula (II-B) can be synthesized from correspondingprecursors, for example the compound (E,E)-farnesylacetone fromnerolidol by a chain-elongation reaction, as described in WO2009/019132.

In one preferred embodiment the group R⁵ does not comprise any chiralcentres. The compound of formula (II-B) is preferred from the groupconsisting of (E)-6,10-dimethylundeca-5,9-dien-2-one,(5E,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one and(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,particularly (5E,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one.

When the group R⁵ comprises chiral centres, it is preferred that thecompound of formula (II-B) is in a form of pure chiral isomers.

This can be either achieved by stereospecific synthesis routes or byisolation of naturally occurring compounds or derived thereof or byseparation from a mixture of the chiral stereoisomers.

For example (6R,10R)-6,10,14-trimethylpentadecan-2-one can be obtainedfrom naturally occurring (R,R)-phytol by oxidation with NaIO₄ and acatalytic amount of RuCl₃ as disclosed by Thomas Eltz et al. in J. Chem.Ecol. (2010) 36:1322-1326.

In another preferred embodiment the compound of formula (II-B) is amethyl ketone having at least a carbon-carbon double bond in theγ,δ-position to the keto group. Preferably it is selected from the groupconsisting of 6-methylhept-5-en-2-one,(E)-6,10-dimethylundec-5-en-2-one, (Z)-6,10-dimethylundec-5-en-2-one,(E)-6,10-dimethylundeca-5,9-dien-2-one,(Z)-6,10-dimethylundeca-5,9-dien-2-one,(E)-6,10,14-trimethylpentadec-5-en-2-one,(Z)-6,10,14-trimethylpentadec-5-en-2-one;(5E,9E)-6,10,14-trimethylpentadeca-5,9-dien-2-one,(5E,9Z)-6,10,14-trimethylpentadeca-5,9-dien-2-one,(5Z,9E)-6,10,14-trimethylpentadeca-5,9-dien-2-one,(5Z,9Z)-6,10,14-trimethylpentadeca-5,9-dien-2-one;(E)-6,10,14-trimethylpentadeca-5,13-dien-2-one,(Z)-6,10,14-trimethylpentadeca-5,13-dien-2-one;(5E,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one,(5E,9Z)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one,(5Z,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one,(5Z,9Z)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one;(E)-6,10,14,18-tetramethylnonadec-5-en-2-one,(Z)-6,10,14,18-tetramethylnonadec-5-en-2-one;(5E,9E)-6,10,14,18-tetramethylnonadeca-5,9-dien-2-one,(5E,9Z)-6,10,14,18-tetramethylnonadeca-5,9-dien-2-one,(5Z,9E)-6,10,14,18-tetra-methylnonadeca-5,9-dien-2-one,(5Z,9Z)-6,10,14,18-tetramethylnonadeca-5,9-dien-2-one;(5E,13E)-6,10,14,18-tetramethylnonadeca-5,13-dien-2-one,(5E,13Z)-6,10,14,18-tetramethylnonadeca-5,13-dien-2-one,(5Z,13E)-6,10,14,18-tetra-methylnonadeca-5,13-dien-2-one,(5Z,13Z)-6,10,14,18-tetramethylnonadeca-5,13-dien-2-one;(E)-6,10,14,18-tetramethylnonadeca-5,17-dien-2-one,(Z)-6,10,14,18-tetramethylnonadeca-5,17-dien-2-one;(5E,9E,13E)-6,10,14,18-tetramethyl-nonadeca-5,9,13-trien-2-one,(5E,9E,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5E,9Z,13E)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5E,9Z,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5Z,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5Z,9E,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one,(5Z,9Z,13E)-6,10,14,18-tetra-methylnonadeca-5,9,13-trien-2-one,(5Z,9Z,13Z)-6,10,14,18-tetramethylnona-deca-5,9,13-trien-2-one;(5E,13E)-6,10,14,18-tetramethylnonadeca-5,13,17-trien-2-one,(5E,13Z)-6,10,14,18-tetramethylnonadeca-5,13,17-trien-2-one,(5Z,13E)-6,10,14,18-tetramethylnonadeca-5,13,17-trien-2-one,(5Z,13Z)-6,10,14,18-tetra-methylnonadeca-5,13,17-trien-2-one;(5E,9E)-6,10,14,18-tetramethylnonadeca-5,9,17-trien-2-one,(5E,9Z)-6,10,14,18-tetramethylnonadeca-5,9,17-trien-2-one,(5Z,9E)-6,10,14,18-tetramethylnonadeca-5,9,17-trien-2-one,(5Z,9Z)-6,10,14,18-tetramethylnonadeca-5,9,17-trien-2-one;(5E,9E,13E)-6,10,14,18-tetramethyl-nonadeca-5,9,13,17-tetraen-2-one,(5E,9E,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5E,9Z,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5E,9Z,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(ZE,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5Z,9E,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5Z,9Z,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5Z,9Z,13Z)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one,(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13-trien-2-one.

In case there are chiral centres in the group R⁵, particularly if R⁵ hasthe formula (III-ARR), the corresponding compounds of formula (II-B) canbe prepared by asymmetrically hydrogenating olefinic unsaturatedprecursors thereof using chiral iridium complexes as disclosed in WO2006/066863 A1 and WO 2012/152779 A1 the entire content of which ishereby incorporated by reference.

In case the compounds just mentioned have chiral carbon centre(s) it ispreferred that said chiral centre(s) has/have the configuration asindicated in formula (III-x).

Preferably the compound of formula (II-B) in this embodiment is(E)-6,10-dimethylundec-5,9-dien-2-one (geranyl acetone) or(Z)-6,10-dimethylundec-5,9-dien-2-one (neryl acetone) or(5E,9E)-6,10,14-trimethylpentadeca-5,9-dien-2-one

(E,E-farnesylacetone) or(5Z,9Z)-6,10,14-trimethylpentadeca-5,9-dien-2-one (Z,Z-farnesylacetone)or (E)-6,10-dimethylundec-5-en-2-one or(Z)-6,10-dimethylundec-5-en-2-one or(E)-6,10,14-trimethylpentadec-5-en-2-one or(Z)-6,10,14-trimethylpentadec-5-en-2-one, preferably geranyl acetone orE,E-farnesyl-acetone or (Z)-6,10-dimethylundec-5-en-2-one or(Z)-6,10,14-trimethylpentadec-5-en-2-one, more preferably geranylacetone or E,E-farnesylacetone.

More preferred the compound of formula (II-B) is6,10-dimethylundecan-2-one or 6,10,14-trimethylpentadecan-2-one.

Most preferred the compound of formula (II-B) is either(6R),10-dimethylundecan-2-one or (6R,10R),14-trimethylpentadecan-2-one.

In one embodiment a compound of formula (II-A) is reacted with a ketalof a compound, i.e. a ketone, of formula (II-B) in the presence either

-   -   of at least one chiral compound of formula (II-C) and of at        least one Brønsted acid having a pK_(a) of between 5 and 10.5,        measured at 25° C. in DMSO;

or

-   -   of at least one chiral compound of formula (II-C-A) having a        pK_(a) of between 5 and 10.5, measured at 25° C. in DMSO, or an        internal salt thereof.

The formation of a ketal from a ketone, per se, is known to the personskilled in the art.

The ketal of a ketone of formula (II-B) can be preferably formed fromthe ketone of formula (II-B) and an alcohol.

It is known to the person skilled in the art that there are alternativeroutes of synthesis for ketals. In principle, the ketal can also beformed by treating a ketone with ortho-esters or by trans-ketalizationsuch as disclosed for example in Pério et al., Tetrahedron Letters 1997,38 (45), 7867-7870, or in Lorette and Howard, J. Org. Chem. 1960,521-525, the entire content of both is hereby incorporated by reference.

Preferably the ketal is formed from the above mentioned ketone offormula (II-B) and an alcohol.

The alcohol can comprise one or more hydroxyl groups. The alcohol may bea phenolic alcohol or an aliphatic or cycloaliphatic alcohol. Preferablythe alcohol has one or two hydroxyl groups.

In case the alcohol has one hydroxyl group, the alcohol is preferably analcohol which has 1 to 12 carbon atoms. Particularly, the alcohol havingone hydroxyl group is selected from the group consisting of methanol,ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-1-propanol,2-butanol, pentane-1-ol, 3-methylbutane-1-ol, 2-methylbutane-1-ol,2,2-dimethylpropan-1-ol, pentane-3-ol, pentane-2-ol,3-methylbutane-2-ol, 2-methylbutan-2-ol, hexane-1-ol, hexane-2-ol,hexane-3-ol, 2-methyl-1-pentanol, 3-methyl-1-pentanol,4-methyl-1-pentanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol,2-methyl-3-pentanol, 2,2-dimethyl-1-butanol, 2,3-dimethyl-1-butanol,3,3-dimethyl-1-butanol, 3,3-dimethyl-2-butanol, 2-ethyl-1-butanol, andall structural isomers of heptanol, octanol and halogenated C₁₋₈-alkylalcohols, particularly 2,2,2-trifluoroethanol. Particularly suitable areprimary or secondary alcohols. Preferably primary alcohols are used asalcohols with one hydroxyl group.

In another embodiment the alcohol is a diol, hence has two hydroxylgroups. Preferably the diol is selected from the group consisting ofethane-1,2-diol, propane-1,2-diol, propane-1,3-diol, butane-1,4-diol,butane-1,3-diol, butane-1,2-diol, butane-2,3-diol,2-methylpropane-1,2-diol, 2,2-dimethylpropane-1,3-diol,1,2-dimethylpropane-1,3-diol, benzene-1,2-diol andcyclohexane-1,2-diols. From two cyclohexane-1,2-diols the preferredstereoisomer is syn-cyclohexane-1,2-diol (=cis-cyclohexane-1,2-diol).

The two hydroxyl group are in one embodiment bound to two adjacentcarbon atoms, hence these diols are vicinal diols. Vicinal diols form a5 membered ring in a ketal.

Particularly suitable are vicinal diols which are selected from thegroup consisting of ethane-1,2-diol, propane-1,2-diol, butane-1,2-diol,butane-2,3-diol, 2-methylpropane-1,2-diol, benzene-1,2-diol andsyn-cyclohexane-1,2-diol, particularly ethane-1,2-diol.

Other particularly suitable are diols, in which the hydroxyl groups areseparated by 3 carbon atoms, and, hence, form a very stable 6 memberedring in a ketal. Particularly suitable diols of this type arepropane-1,3-diol, butane-1,3-diol, 2-methylpropane-1,3-diol,2-methylbutane-1,3-diol, 2,2-dimethylpropane-1,3-diol,1,2-dimethylpropane-1,3-diol, 3-methylpentane-2,4-diol and2-(hydroxymethyl)-cyclohexanol.

Preferably primary alcohols are used as diols.

The reaction conditions and stoichiometry used for the ketal formationare known to the person skilled in the art.

It is more preferred that the compound of formula (I I-C) is selectedfrom the group consisting of

The pK_(a) of the Brønsted acid having a pK_(a) of between 5 and 10.5,can be measured at 25° C. in DMSO and is used in combination withcompound of formula (II-C).

Suitable Brønsted acids are particularly those mentioned in table II inBordwell, Acc. Chem. Res. 1988, 21, 456-463 having a pK_(a) of between 5and 10.5.

Preferred is that the Brønsted acid is selected from the groupconsisting of trifluormethane sulphonamide, p-nitrobenzoic acid,3,5-dinitrobenzoic acid and 3,5-bis(trifluoromethyl)benzoic acid, morepreferably from the group consisting of trifluormethane sulphonamide andp-nitrobenzoic acid.

Most preferred is the Brønsted acid either trifluormethane sulphonamideor p-nitrobenzoic acid.

It is preferred that the ratio of molar amounts of Brønsted acid tochiral compound of formula (II-C) is between 1:2 and 4:1, preferably inthe range from 1:1 and 2:1. It is, furthermore, preferred that the ratioof Brønsted acid to chiral compound of formula (II-C) is selected sothat slightly more than one acid proton from the Brønsted acid isavailable per NH group of the compound of formula (II-C).

In the second embodiment of the invention the reaction between compoundof formula (II-A) and compound of formula (II-B) or a ketal thereof isdone in the presence of at least one chiral compound of formula (II-C-A)having a pK_(a) of between 5 and 10.5, measured at 25° C. in DMSO, or aninternal salt thereof.

The substituent A in the formulae of this document represents asubstituent carrying a Brønsted acid functional group. The substituentcarrying a Brønsted acid functional group is particularly an alkylenegroup having 1 to 6 carbon atoms and optionally oxygen atoms in thealkylene chain, carrying a Brønsted acid functional group. Preferablysuch a substituent A is an alkylene group with 1 to 3 carbon atoms, mostpreferably a methylene group, carrying a Brønsted acid functional group.

It is preferred that the substituent A carries one Brønsted acidfunctional group.

The compound of formula (II-C-A) is most preferably the compound offormula (IV)

The compounds of formula (II-C) and (II-C-A) are chiral compounds. Thecompounds are either used directly as pure stereoisomers or separated byknown techniques into the R- and the S-stereoisomer prior to the use forthe present invention.

It has been found that the isomer shown in formula (II-C), respectively(II-C-A), yields preferentially the isomers of compound of formula (I),respectively of formula (V), showing the R-configuration at the chiralcentre indicated by *.

Therefore, it has been found that the chirality of the compound offormula (II-C) or of formula (II-C-A) has an important effect on thechirality of the compound being formed, i.e. on compound of formula (I)or of formula (V).

Hence, the isomer having the R-configuration at the chiral centre markedby * in formula (I) is preferentially formed in respect to thecorresponding isomer having the S-configuration at said chiral centre bythe above process.

On the other hand, it has been found that when using the stereoisomersshown in formula (II-C′), respectively (II-C-A′), instead of compoundsof formula (II-C), respectively (II-C-A), preferentially the isomers ofcompound of formula (I) resp. formula (V) showing the S-configuration atthe chiral centre indicated by * are obtained.

Compound of formula (II-A) and compound of formula (II-B) or a ketalthereof are reacted either in the presence of at least one chiralcompound of formula (II-C) and of at least one Brønsted acid having apK_(a) of between 5 and 10.5, measured at 25° C. in DMSO or in thepresence of at least one chiral compound of formula (II-C-A) having apK_(a) of between 5 and 10.5, measured at 25° C. in DMSO, or an internalsalt thereof.

This reaction occurs in an organic solvent. In one embodiment thereaction is undertaken in an organic solvent which is a hydrocarbon,preferably in an aromatic hydrocarbon, particularly in toluene,particularly at a temperature of preferably between 80° C. and 150° C.,more preferably of between 90° C. and 140° C., most preferably at atemperature of between 100 and 110° C. at ambient pressure. It ispreferred that the reaction temperature is about 5 to 10° C. below theboiling point of the solvent.

In another embodiment the reaction is undertaken in an organic polarsolvent which is selected from the group consisting of alcohols, ethers,esters, carbonitriles, halogenated hydrocarbons and lactams.Particularly suitable polar solvents are acetonitrile, ethyl acetate,methanol, ethanol, dichloromethane, tetrahydrofuran (THF),N-methylpyrrolidone (NMP), 1,2-dichloroethane, 2,2,2-trifluoroethanoland isopropanol. However, it has been observed that the water, being aninorganic polar solvent, is not suitable as solvent because noconversion was detected.

Furthermore, it has been shown that the amount of organic solvent ispreferably chosen so that at least a 4% by weight solution of compoundof formula (II-A) is obtained. In a preferred embodiment the weightratio between compound of formula (II-A) and organic solvent is between2:98 and 80:20, particularly between 3:97 and 50:50, preferably between4:96 and 30:70.

It has been found that the lower the temperature for the reaction ofcompound of formula (II-A) and compound of formula (II-B) or a ketalthereof is, the higher the chiral purity of the compound of formula (I)resp. (V) in view of chirality at the chiral centre indicated by * is.This chiral purity is expressed by the enantiomeric excess (ee) beingdetermined by the absolute value of the difference of amounts of the Rand S isomers divided by the sum of amounts of both isomers: and isnormally expressed in %.

${ee} = {{abs}\left( \frac{\lbrack R\rbrack - \lbrack S\rbrack}{\lbrack R\rbrack + \lbrack S\rbrack} \right)}$

We have been able to show that by using a reaction temperature of 0° C.the process has yielded in the formation of a product having anenantiomeric excess up to 40%, corresponding to a ratio of [R]/[S] of2.3. However, the reaction rate was rather low.

In view of reaction rate, it is preferred to have the reaction takingplace at higher temperatures higher than 0° C.

Furthermore, it might be helpful, particularly in the case where at lowreaction temperatures are used, to use molecular sieves in the reactionmedium.

The enantiomeric ratio can be increased further by optimizing thereaction conditions. The larger the enantiomeric ratio is the better.However, also at lower enantiomeric ratios the invention can beadvantageous as the complete separation of the isomers, such as bychromatography, particularly by chromatography using chiral stationaryphases, needs much less efforts as compared to a racemic mixture. Hence,the enantiomeric ratio should be at least 15%, preferably at least 20%,more preferably at least 25%.

In a further aspect, the invention relates to a process of manufacturinga compound of formula (V) comprising the steps

-   -   i) process of manufacturing of formula (I) as it has been        described in detail above;    -   ii) reducing of compound of formula (I)

The substituents R¹, R², R³, R⁴ and R⁵ are already discussed in detailabove.

Most preferably the chiral isomers of formula (V) are the isomersselected from the group consisting of

-   α-Tocopherol (R¹=R³=R⁴=CH₃, R⁵=(II-A), particularly (II-ARR), R²=H),-   β-Tocopherol (R¹=R⁴=CH₃, R³=H, R⁵=(II-A), particularly (II-ARR),    R²=H),-   γ-Tocopherol (R¹=H, R³=R⁴=CH₃, R⁵=(II-A), particularly (II-ARR),    R²=H),-   δ-Tocopherol (R¹=R³=H, R⁴=CH₃, R⁵=(II-A), particularly (II-ARR),    R²=H),-   α-Tocotrienol (R¹=R³=R⁴=CH₃, R⁵=(II-B), R²=H),-   β-Tocotrienol (R¹=R⁴=CH₃, R³=H, R⁵=(II-B), R²=H),-   γ-Tocotrienol (R¹=H, R³=R⁴=CH₃, R⁵=(II-B), R²=H),-   δ-Tocotrienol (R¹=R³=H, R⁴=CH₃, R⁵=(II-B), R²=H), and the esters,    particularly the acetates (R²=COCH₃), or phosphates thereof.

Particularly preferred compounds of formula (V) are esters of organicand inorganic acids. Examples of esters of organic acids are acetate andsuccinate esters, esters of inorganic esters are tocopheryl phosphates,ditocopheryl phosphates, particularly a-tocopheryl phosphate anda-ditocopheryl phosphate.

Most preferred compounds of formula (V) are tocopherols and tocopherylacetates.

The reduction in step ii) can be made by different ways. Typically it isreduced by using a reduction means.

Preferably the reduction is made by metallic zinc in the presence of anacid or an acid mixture, for example as disclosed for in U.S. Pat. No.6,096,907 or EP 0 989 126 the whole disclosure of which is incorporatedherein by reference.

The reduction step ii) is typically done in stirred vessel under inertatmosphere. It is further preferred that the step ii) is done at atemperature in the range of 30 to 90° C., particularly between 40 and65° C.

After completion of the reaction the compound of formula (V) ispurified, particularly by means of extraction.

It has been observed that the reduction of compound of formula (I) tocompound of formula (V) does not modify the chirality of the chiralcentre indicated by * in the formulae (I) resp. (V).

It has been found that the isomer shown in formula (II-C), respectively(II-C-A), yields preferentially the isomers of compound of formula (I),respectively of formula (V), showing the R-configuration at the chiralcentre indicated by *.

Hence, the isomer having the R-configuration at the chiral centre markedby * in formula (V) is preferentially formed in respect to thecorresponding isomer having the S-configuration at said chiral centre.

On the other hand, it has been found that when using the stereoisomersshown in formula (II-C′), respectively (II-C-A′), instead of compoundsof formula (II-C), respectively (II-C-A), preferentially the isomers ofcompound of formula (I) resp. formula (V) showing the S-configuration atthe chiral centre indicated by * are obtained.

In a further aspect, the invention relates to a composition comprising

-   a) at least one compound of formula (II-A) and-   b) at least one ketone of formula (II-B) or a ketal thereof and-   c) at least one organic solvent and-   either    -   a mixture or reaction product of        -   d) at least one chiral compound of formula (II-C) and        -   e) at least one Brønsted acid having a pK_(a) of between 5            and 10.5, measured at 25° C. in DMSO;-   Or    -   e) at least one chiral compound of formula (II-C-A) having a        pK_(a) of between 5 and 10.5, measured at 25° C. in DMSO, or an        internal salt thereof

The substituents R¹, R^(2′), R³, R⁴, R⁵, Y¹ and A have already beendiscussed in detail above.

Furthermore, details for the compound of formula (II-A), for compound offormula (II-B) or a ketal thereof, for chiral compound of formula (II-C)and for chiral compound of formula (II-C-A) as well their preferredembodiments and their ratios have been discussed in detail alreadyabove.

As described above this composition is very suitable for the synthesisof compound of formula (I) which can be transformed to compound offormula (V).

As has been shown above in great detail, the present invention relatesto the manufacturing of compounds of formula (I).

6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)chroman-4-one. Asthis compound, being represented by formula (VI), is not yet known, itrepresents a further aspect of the present invention.

It has been shown that compound of formula (VI) can be manufactured in astereospecific matter in view of the 2-position in the chromanones ringand that it can be easily converted to γ-tocopherol.

Therefore, a chiral compound of formula (II-C) can be used for thepreparation of tocopherols or tocotrienols as it also discussed in greatdetail above. This use particularly involves the use of of a chiralcompound of formula (II-C) for the preparation of compound of formula(I) followed by transformation to compound of formula (V). When this useis made in the presence of at least one Brønsted acid having a pK_(a) ofbetween 5 and 10.5, measured at 25° C. in DMSO the formation of thestereoisomer of formula (I) resp. (V) having the R configuration at thechiral carbon centre marked by * in formula (I) resp. (V) is obtained inan excess related to the corresponding stereoisomer having theS-configuration.

The details for chiral compound of formula (II-C), for compound offormula (I), for formula (V) and for one Brønsted acid as well theirpreferred embodiments and their ratios have been discussed in detailalready above.

EXAMPLES

The present invention is further illustrated by the followingexperiments.

Use of Different Acids

0.5 mmol of 2-acetyl-3,5,6-trimethylhydroquinone and 0.795 mmol of theacid indicated in table 1 have been suspended in a 20 mL round bottomflask equipped with a magnetic stirring bar, heating device, waterseparator and argon supply at 23° C. in 2.5 mL (23.5 mmol) toluene. Then0.514 mmol of E,E-farnesyl-acetone has been is added and finally 0.795mmol (S)-2-(methoxymethyl)-pyrrolidine. The reaction mixture has beenstirred for the time at the temperature as indicated in table 1. Whileheating to 120° C. water is distilled off and the reaction mixture wasgetting brown. After the indicated time, the reaction mixture was cooledto 23° C. Then 1 mL of 2 N HCl has been added and the mixture has beentransferred to a separation funnel and was well shaken. The toluenephase was separated and washed with portions of 10 mL water until aneutral water phase was obtained. The organic layers are dried oversodium sulfate, filtered and concentrated at 40° C. and 10 mbar.

The product formed and isolated by column chromatography on SiO₂ hasbeen identified to be6-hydroxy-2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-4-one:

¹H NMR (CDCl₃, 300 MHz) δ 1.30 (s, 3H); 1.51 (s, 6H); 1.52 (s, 3H);1.54-1.58 (m, 1H); 1.61 (d, J=0.9 Hz, 3H); 1.67-1.78 (m, 1H); 1.67-2.10(m, 10H); 2.08 (s, 3H); 2.16 (s, 3H); 2.48 (s, 3H); 2.51 (d, J=15.8 Hz,1H); 2.68 (d, J=15.8Hz, 1H), 4.45 (s br, 1 H); 4.99-5.05 (m, 3H) ppm.

¹³C NMR (CDCl₃, 75.5 MHz) δ 12.1; 12.8; 13.3; 15.9; 16.0; 17.7; 22.2;23.7; 25.1; 26.6; 26.8; 39.4; 39.7 (2C); 49.5; 79.4; 116.7; 120.4;123.5; 124.0; 124.1; 124.4; 131.3; 132.0; 135.1; 135.7; 145.8; 152.8;195.2 ppm.

Determination of enantiomeric ratio: HPLC, Chiralcel® OD-H, 250×4.6 mm,10 mL EtOH, 990 mL n-hexane, 1.0 mL/min; detection at 220 nm.

TABLE 1 Different Brønsted acids. pKa Yield¹ ee Acid (in DMSO)t_(23° C.) t_(120° C.) [%] [R]:[S] [%] Ref. 1 none 20 1.5 2.2 50:50 0Ref. 2 trifluoromethanesulfonic 1 20 1 dec.² — 0 acid Ref. 3(−)-camphorsulfonic acid 1.6 20 2 4 50:50 0 1 dichloroacetic acid 6.4 1724 8 59:41 18 2 3,5-dinitro- 7.4 16 18 33 63:37 26 benzoic acid 34-nitrobenzoic acid 9.0 16 2 41 63:37 26 4 3,5-bis(trifluoromethyl)- 9.116 2 34 63:37 26 benzoic acid 5 trifluoromethane- 9.7 20 1 9 60:40 20sulfonamide Ref. 4 benzoic acid 11.0 20 1.5 28 52:48 4 Ref. 5 aceticacid 12.3 20 1.5 2 52:48 4 Ref. 6 p-toluenesulfonamide 16.1 20 1 1250:50 0 Ref. 7 (1S)-10-camphor- 17 20 2 2 50:50 0 sulfonamide Ref. 8methanesulfonamide 17.5 20 1 20 50:50 0 ¹yield relative to2-acetyl-3,5,6-trimethylhydroquinone ²dec. = decomposition

Use of Different Pyrrolidines

0.5 mmol of 2-acetyl-3,5,6-trimethylhydroquinone and 0.795 mmol ofp-nitrobenzoic acid have been suspended in a 20 mL round bottom flaskequipped with a magnetic stirring bar, heating device, water separatorand argon supply at 23° C. in 2.5 mL toluene. Then 0.514 mmol ofE,E-farnesylacetone is added and finally 0.795 mmol of the baseindicated in table 2. The reaction mixture has been stirred for 16 h at23° C. followed by 2 h at 120° C. While heating to 120° C. water isdistilled off and the reaction mixture was getting brown. Then, thereaction mixture was cooled to 23° C. and 1 mL of 2 N HCl has been addedand the mixture has been transferred to a separation funnel and was wellshaken. The toluene phase was separated and washed with portions of 10mL water until a neutral water phase was obtained. The organic layersare dried over sodium sulfate, filtered and concentrated at 40° C. and10 mbar.

The product formed has been identified to be6-hydroxy-2,5,7,8-tetra-methyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-4-one(characterization see point “use of different acids”).

TABLE 2 Different bases, particularly pyrrolidine derivatives. Yield¹ eeBase [%] [R]:[S] [%] Ref. 9 pyrrolidine 59 50:50 0 Ref. 10(S)-pyrrolidin-2-ylmethanamine 33 50:50 0 Ret. 11 N-methylpyrrolidine 0—² —²  6 (S)-2,6-dimethyl-N-(pyrrolidin- 17 63:37 26 2-ylmethyl)aniline 7 (S)-tert-butyl (pyrrolidin-2- 55.8 55:45 10 ylmethyl)carbamate  8(S)-pyrrolidin-2-ylmethanol 4.1 58:42 16  9(S)-2-(ethoxymethyl)pyrrolidine 59 64:36 28 10(S)-1-(pyrrolidin-2-ylmeth- 28 55:45 10 yl)pyrrolidine Ref. 12(2S,5S)-2,5-bis(methoxymeth- 0 —² —² yl)pyrrolidine Ref. 13(S)-2-(tert-butyl)-3-meth- 0 —² —² ylimidazolidin-4-one Ref. 14(S)-diphenyl(pyrrolidin-2- 0 —² —² yl)methanol ¹yield relative to2-acetyl-3,5,6-trimethylhydroquinone ²as no reaction occurred (yield:0%) no measurements were possible.

Use of Chiral Pyrrolidines Carrying a Brønsted Acid Functional Group

0.5 mmol of 2-acetyl-3,5,6-trimethylhydroquinone and 0.795 mmol of(S)-1,1,1-trifluoro-N-(pyrrolidin-2-ylmethyl)methanesulfonamide havebeen suspended in a 20 mL round bottom flask equipped with a magneticstirring bar, heating device, water separator and argon supply at 23° C.in 2.5 mL toluene. Then 0.514 mmol of E,E-farnesylacetone is added. Thereaction mixture has been stirred for 16 h at 23° C. followed by 2 h at120° C. While heating to 120° C. water is distilled off and the reactionmixture was getting brown. Then, the reaction mixture was cooled to 23°C. and 1 mL of 2 N HCl has been added and the mixture has beentransferred to a separation funnel and was well shaken. The toluenephase was separated and washed with portions of 10 mL water until aneutral water phase was obtained. The organic layers are dried oversodium sulfate, filtered and concentrated at 40° C. and 10 mbar.

The product formed has been identified to be6-hydroxy-2,5,7,8-tetra-methyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-4-one.The product was obtained in 58% yield and showed an enantiomeric ratioof 61:39 (corresponding to an ee of 22%).

Use of Different Substrates to be Condensed

0.5 mmol of compound of formula (II-A), having the groups R³=R⁴=CH₃ andR¹ and R^(2′) as indicated in table 3, and 0.795 mmol of3,5-dinitrobenzoic acid have been suspended in a 20 mL round bottomflask equipped with a magnetic stirring bar, heating device, waterseparator and argon supply at 23° C. in 2.5 mL toluene. Then 0.514 mmolof compound of formula (II-B), having the group R⁵ as indicated in table3, has been is added and finally 0.795 mmol(S)-2-(methoxymethyl)pyrrolidine. The reaction mixture has been stirredduring 16 hours at 23° C. While heating to 120° C. water is distilledoff and the reaction mixture was getting brown. After the indicatedtime, the reaction mixture was cooled to 23° C. Then 1 mL of 2 N HCl hasbeen added and the mixture has been transferred to a separation funneland was well shaken. The toluene phase was separated and washed withportions of 10 mL water until a neutral water phase was obtained. Theorganic layers are dried over sodium sulfate, filtered and concentratedat 40° C. and 10 mbar.

The identity of the product formed has been proven by NMR and the

the ratio of [2R] to [2S] stereoisomers has been determined by HPLC:Chiralcel® OD-H, 250×4.6 mm, 10 mL EtOH, 990 mL n-hexane, 1.0 mL/min;detection at 220 nm.

TABLE 3 t_(23°C.) t_(120°C.) Yield [R]: R^(2′) R¹ R³ R⁴ R⁵ [h] [h] [%][S] 11 C(O)CH₃ CH₃ CH₃ CH₃ C₁₆H₂₇ ³ 17  2 25¹ 63:37 12 C(O)CF₃ CH₃ CH₃CH₃ C₁₆H₂₇ ³ 16 18  1¹ 63:37 13 H CH₃ CH₃ CH₃ C₁₆H₃₃ ⁴ 16  2 90² 63:3714 H H H H C₁₆H₃₃ ⁴ 16  2 26² 67:33 Different staring materials. ¹yield:based on sum of the ester derivative plus the free phenol formed bypartial hydrolysis of the ester during the reaction and work-up;relative to compound of formula (II-A); ²yield relative to compound offormula (II-A) ³

⁴

Synthesis of6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)chroman-4-one (15)(Compound of Formula (VI)

2.5 mmol of 1-(2,5-dihydroxy-3,4-dimethylphenyl)ethanone and 4.0 mmol4-nitrobenzoic acid were suspended in a 25 mL round bottom flaskequipped with a magnetic stirring bar, heating device, water separatorand argon supply at 23° C. in 12.5 mL toluene. To this brown suspension2.58 mmol of E,E-farnesylacetone and afterwards 4.0 mmol(S)-2-(methoxymethyl)pyrrolidine were added. The temperature of thereaction mixture rose to 25° C., then stirring was continued for 17.5 hat 23° C. Then the mixture was heated to reflux (150° C. oil bathtemperature, internal temp. 116° C.), and water was distilled off (thewater separator was filled with toluene before). The reaction mixturewas cooled to 23° C. Then 5 mL of 2 N HCl were added, the mixturestirred for 15 min, transferred to a separation funnel and well shaken.The toluene phase was separated and washed successively with fourportions of 15 mL water each until a neutral water phase was obtained.The organic layer was dried over sodium sulfate, filtered, concentratedat 50° C. and 20 mbar, and dried at 23° C. and 0.02 mbar for 2 h.

The crude product (1.271 g black oil with solids) was purified by columnchromatography (100 g silica gel 60, n-hexane/EtOAc 9:1). Afterevaporation (40° C. and 20 mbar) and drying at 24° C. and 0.022 mbar for2 h 6-hydroxy-2,7,8-tri-methyl-2-(4,8,12-trimethyltridecyl)chroman-4-one(15) was obtained (0.672 g black oil, purity 91.7wt % by NMR, 97.1 area% by GC, yield 57%).

¹H NMR (CDCl₃, 300 MHz) δ 0.80-0.90 (m, 4 CH₃); 0.98-1.83 (m, 21 aliph.H); 1.37 (s, CH₃); 2.16 (s, 1 arom. CH₃); 2.22 (s, 1 arom. CH₃); 2.590and 2.596 (d, J=16.5 and 16.6 Hz, 1H); 2.72 (d, J=16.7 Hz, 1H), 4.88 (s,OH); 7.12 (s, 1 H_(arom)) ppm.

¹³C NMR (CDCl₃, 75.5 MHz) δ 11.9; 13.0; 19.52; 19.58; 19.67; 19.73;21.0; 22.62; 22.71; 23.88; 23.90; 24.4; 24.8; 28.0; 32.6; 32.8; 37.08;37.17; 37.22; 37.28; 37.38; 37.43; 39.4; 39.54; 39.64; 47.60; 47.64;80.6; 107.2; 117.6; 127.3; 128.2; 129.0; 133.9; 147.7; 152.4; 193.6 ppm.

MS (trimethylsilyl derivative): m/e=502 (M⁺), 487 ([M-15]⁺), 277 (100%),237.

Determination of the ratio of [2R]-stereoisomers to [25]-stereoisomers:HPLC, Chiralpak® IC, 250×4.6 mm, 10 mL EtOH, 990 mL n-hexane, 1.0mL/min; detection at 220 nm; [2R]:[2S]=57:43.

Use of Different Solvents

0.5 mmol of 2-acetyl-3,5,6-trimethylhydroquinone and 0.795 mmol ofp-nitrobenzoic acid have been suspended in a 20 mL round bottom flaskequipped with a magnetic stirring bar, heating device, 4 Å molecularsieve and argon supply at 23° C. in 2.5 mL of the solvent indicated intable 4. Then 0.514 mmol of E,E-farnesylacetone has been is added andfinally 0.795 mmol (S)-2-(methoxymethyl)pyrrolidine. The reactionmixture has been stirred for 24 h at 40° C. Then the reaction mixturewas cooled to 23° C. Then 1 mL of 2 N HCl has been added and the mixturehas been transferred to a separation funnel and was well shaken. Thetoluene phase was separated and washed with portions of 10 mL wateruntil a neutral water phase was obtained. The organic layers are driedover sodium sulfate, filtered and concentrated at 40° C. and 10 mbar.

The product formed has been identified to be6-hydroxy-2,5,7,8-tetra-methyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-4-one(characterization see point “use of different acids”).

TABLE 4 Different solvents. Yield¹ ee Solvent [%] [R]:[S] [%] 16 ethylacetate 14 63:37 26 17 isopropanol 19 60:40 20 18 2,2,2-trifluoroethanol1 67:33 34 19 1,2-dichloroethane 7 65:35 30 20 N-methylpyrrolidone 1663:37 26 21 propylene carbonate 10 67:33 34 Ref. 15 water 0 —2 —2 ¹yieldrelative to 2-acetyl-3,5,6-trimethylhydroquinone 2as no reactionoccurred (yield: 0%) no measurements were possible.

Conversion of Chromanones to Chromans

6-hydroxy-2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-4-onebeen transformed to α-tocotrienol by treatment with zinc dust andaqueous hydrochloric acid, as described in detail by Baldenius et al.,EP 0 989 126 A1:

6-Hydroxy-2,5,7,8-tetramethyl-2-((3E,7E)-4,8,12-trimethyltrideca-3,7,11-trien-1-yl)chroman-4-one(5.0 mmol) (example 2) was dissolved under an argon atmosphere in 25 mLtoluene, and 25% aqueous HCl (41.7 mL, 340 mmol) was added. To thismechanically stirred two-phasic mixture zinc dust (65 mmol) was added insmall portions (ca. 0.5 g) during 4 h. Stirring was continued at 40° C.for 16 h and at 65° C. for 1 h. After completion of the reaction (TLCcontrol), the mixture was cooled to room temperature and filteredthrough a pad of Dicalite. The filter residue was washed with 100 mLn-heptane, and the combined filtrates washed with 50 mL water. Theorganic layer was dried over sodium sulfate, filtered, concentrated at40° C. and 10 mbar and dried for 2 h at 0.003 mbar at 23° C. The 2.22 gyellowish-brown oil was purified by column chromatography (100 g SiO₂silica gel 60, n-hexane/EtOAc 9:1). After evaporation (40° C./20 mbar)and drying (0.021 mbar/23° C.) α-tocotrienol was obtained as ayellowish-brown oil (1.291 g, purity 93.9wt %, yield 57%).

The compound obtained showed identical retention time in comparison toan authentic sample of natural (R,E,E)-α-tocotrienol, and the valuesobtained by measuring the ¹H NMR (CDCl₃, 300 MHz) were identical withthe values for α-tocotrienol, as for example reported by P. Schudel etal., Helv. Chim. Acta 1963, 46, 2517-2526.

Determination of enantiomeric ratio: HPLC, Chiralcel® OD-H, 250×4.6 mm,0.5% EtOH in n-hexane, 1.0 mL/min; detection at 220 nm.

In analogy to the example given above,6-hydroxy-2,7,8-trimethyl-2-(4,8,12-trimethyltridecyl)chroman-4-one(example 15) has been transformed to γ-tocopherol by treatment with zincdust and aqueous hydrochloric acid, as described by Baldenius et al., EP0 989 126 A1. The compound obtained showed identical retention time incomparison to an authentic sample of γ-tocopherol, and the valuesobtained by measuring the ¹H NMR (CDCl₃, 300 MHz) were identical withthe values for γ-tocopherol, as for example reported by J. K. Baker andC. W. Myers, Pharmaceutical Research 1991, 8, 763-770.

In analogy to the example given above,6-hydroxy-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)chroman-4-one(example 13) has been transformed to α-tocopherol by treatment with zincdust and aqueous hydrochloric acid, as described by Baldenius et al., EP0 989 126 A1. The compound obtained showed identical retention time incomparison to an authentic sample of α-tocopherol, and the valuesobtained by measuring the ¹H NMR (CDCl₃, 300 MHz) were identical withthe values for α-tocopherol, as for example reported by J. K. Baker andC. W. Myers, Pharmaceutical Research 1991, 8, 763-770.

1. Process for the manufacturing of a compound of formula (I)

comprising the step of reacting a compound of formula (II-A) and acompound of formula (II-B) or a ketal thereof in the presence of anorganic solvent and either of at least one chiral compound of formula(II-C) and of at least one Brønsted acid having a pK_(a) of between 5and 10.5, measured at 25° C. in DMSO; or of at least one chiral compoundof formula (II-C-A) having a pK_(a) of between 5 and 10.5, measured at25° C. in DMSO, or an internal salt thereof

wherein R¹, R³ and R⁴ are independently from each other hydrogen ormethyl groups; R² and R^(2′) represents hydrogen or a phenol protectiongroup; R⁵ represents either a linear or branched completely saturatedC₆₋₂₅-alkyl group or a linear or branched C₆₋₂₅-alkyl group comprisingat least one carbon-carbon double bond; Y¹ represents either CH₂Y² or

wherein R⁶ represents a linear or branched C₁₋₁₂-alkyl group whichoptionally further comprises at least one aromatic group and/or C═Oand/or NH and/or NH₂ group; Y² represents either OH or OR⁷ or NHR⁷ orNHCOOR⁷ or

wherein R⁷ represents either a linear or branched C₁₋₁₂-alkyl groupwhich optionally further comprises at least one aromatic group and/orC═O and/or NH and/or NH₂ group or an aryl group or a substituted arylgroup or a heteroaryl group or a substituted heteroaryl group and Arepresents a substituent carrying a Brønsted acid functional group andthe dotted line(s) represents the bond(s) by which the correspondingsubstituent is bound to the rest of formula (II-C); and wherein *represents the chiral centre of the chiral isomer of formula (I). 2.Process according to claim 1 wherein R⁵ is of formula (III)

wherein m and p stand independently from each other for a value of 0 to5 provided that the sum of m and p is 1 to 5, and where thesubstructures in formula (III) represented by s1 and s2 can be in anysequence; and the dotted line represents the bond by which thesubstituent of formula (III) is bound to the rest of the compound offormula (II-B) or formula (I); and wherein # represents a chiral centre,obviously except in case where said centre is linked to two methylgroups.
 3. Process according to claim 1 whereinR¹=R³=R⁴=CH₃ orR¹=R⁴=CH₃, R³=H orR¹=H, R³=R⁴=CH₃ orR¹=R³=H, R⁴=CH₃.
 4. Process according to claim 1 wherein the compound offormula (II-C) is selected from the group consisting of


5. Process according to claim 1 wherein the Brønsted acid is selectedfrom the group consisting of trifluormethane sulphonamide,p-nitrobenzoic acid, 3,5-dinitrobenzoic acid and3,5-bis(trifluoromethyl)benzoic acid.
 6. Process according to claim 1wherein the ratio of molar amounts of Brønsted acid to chiral compoundof formula (II-C) is between 1:2 and 4:1, preferably in the range from1:1 and 2:1.
 7. Process according to claim 1 wherein the compound offormula (II-C-A) is the compound of formula (IV)


8. Process of manufacturing a compound of formula (V) comprising thesteps i) process of manufacturing of formula (I) according to claim 1;ii) reducing of compound of formula (I)


9. Process according to claim 1, wherein the isomer having theR-configuration at the chiral centre marked by * in formula (I) or (V)is preferentially formed in respect to the corresponding isomer havingthe S-configuration at said chiral centre.
 10. Composition comprising a)at least one compound of formula (II-A) and b) at least one ketone offormula (II-B) or a ketal thereof and c) at least one organic solventand either a mixture or reaction product of d) at least one chiralcompound of formula (II-C) and e) at least one Brønsted acid having apK_(a) of between 5 and 10.5, measured at 25° C. in DMSO; or e) at leastone chiral compound of formula (II-C-A) having a pK_(a) of between 5 and10.5, measured at 25° C. in DMSO, or an internal salt thereof

wherein R¹, R³ and R⁴ are independently from each other hydrogen ormethyl groups; R^(2′) represents hydrogen or a phenol protection group;R⁵ represents either a linear or branched completely saturatedC₆₋₂₅-alkyl group or a linear or branched C₆₋₂₅-alkyl group comprisingat least one carbon-carbon double bond; Y¹ represents either CH₂Y² or

wherein R⁶ represents a linear or branched C₁₋₁₂-alkyl group whichoptionally further comprises at least one aromatic group and/or C═Oand/or NH and/or NH₂ group; Y² represents either OH or OR⁷ or NHR⁷ orNHCOOR⁷ or

wherein R⁷ represents either a linear or branched C₁₋₁₂-alkyl groupwhich optionally further comprises at least one aromatic group and/orC═O and/or NH and/or NH2 group or an aryl group or a substituted arylgroup or a heteroaryl group or a substituted heteroaryl group and Arepresents a substituent carrying a Brønsted acid functional group andthe dotted line(s) represents the bond(s) by which the correspondingsubstituent is bound to the rest of formula (II-C).
 11. Compositionaccording to claim 10, wherein R⁵ is of formula (III)

wherein m and p stand independently from each other for a value of 0 to5 provided that the sum of m and p is 1 to 5, and where thesubstructures in formula (III) represented by s1 and s2 can be in anysequence; and the dotted line represents the bond by which thesubstituent of formula (III) is bound to the rest of compound of formula(II-B); and wherein # represents a chiral centre, obviously except incase where said centre is linked to two methyl groups.
 12. Compositionaccording to claim 10 wherein the compound of formula (II-C) is selectedfrom the group consisting of


13. Composition according to anyone of the preceding claims 10 to 12wherein the Brønsted acid is selected from the group consisting oftrifluormethane sulphonamide, p-nitrobenzoic acid, 3,5-dinitrobenzoicacid and 3,5-bis(trifluoromethyl)benzoic acid.
 14. Composition accordingto claim 10 wherein the ratio of molar amounts of Brønsted acid tochiral compound of formula (II-C) is between 1:2 and 4:1, preferably inthe range from 1:1 and 2:1. 15.6-hydroxy-2,7,8-tri-methyl-2-(4,8,12-trimethyltridecyl)chroman-4-one.